Chemoselective preparation of 1,2,3-triazole-isoxazole bisfunctional derivatives and their application in peptidomimetic synthesis

Article abstract of DOI:10.1039/c2ob26990b

A novel kind of bisfunctional nitrogen heterocycle containing both 1,2,3-triazole and isoxazole scaffolds has been prepared. The protocol utilized alkynyl substituted amines as the bifunctional linkers to combine a copper-free triazole synthesis with a hypervalent iodine-mediated isoxazole cycloaddition through a chemoselective process. This method has also been exemplified in the construction of bisfunctional-modified peptidomimetics by combining three reactions in a sequential procedure. This straightforward metal free process may find biological applications. In addition, all of the compounds were analysed by Lapinski's rule-of-five which is expected to help drug discovery.

Full text of DOI:10.1039/c2ob26990b

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ARTICLE TYPE
Chemoselective Preparation of 1,2,3-triazole and Isoxazoles
Bisfunctional Derivatives and Its Application in Peptidomimetic
Synthesis
Teng-fei Niua, Mei-fang Lva, Liang wangb, Wen-bin Yia, and Chun Caia*
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
A novel kind of bisfunctional nitrogen heterocycles containing both 1,2,3ꢀtriazole and isoxazole scaffolds
has been prepared. The protocol utilized alkynyl substituted amines as the bifunctional linkers to conjunct
a copperꢀfree triazole synthesis with a hypervalent iodineꢀmediated isoxazole cycloaddition through
10 chemoselective process. This method also been exemplified in construction of bisfunctionalꢀmodified
peptidomimetics by combing of three reactions in sequential procedure. The metal free straightforward
process may be of biological applications. In addition, all of the compounds were analysed by Lapinski’s
ruleꢀofꢀfive which is expected to help drug discovery.
1,2,3ꢀtrazoles (Fig.1).13 The protocol utilized alkynyl substituted
45 amines as the bifunctional linkers reacting with azides as well as
diketene which could undergo a threeꢀcomponent cycloaddition
to form 5ꢀmethylꢀ1Hꢀ1,2,3ꢀtriazole. There were non Husigen 1,3ꢀ
dipolar cycloaddition products were found, each resulting 1,2,3ꢀ
trazoles scaffold contains an alkyne group that provides further
50 opportunities to generate complex bisfunctional molecules
through chemoselective sequential reactions.
Herein, we demonstrated an efficient chemoselective synthesis
of complex nitrogen heterocycles containing both 1,2,3ꢀtriazole
and isoxazoles motifs. In addition, we also explored and took
55 advantage of this chemoselective reaction in order to access
Introduction
15 Nitrogen heterocycles have been received much attention for
biological probes and pharmaceutical lead discovery. 1,2,3ꢀ
triazole and isoxazole scaffolds form a major class of nitrogen
heterocycles which have generated considerable synthetic interest
due to their occurrence in diverse natural products and notable
20 biological activity. It is reported that, 1,2,3ꢀtriazoles can act as
anticancer medications1, antibacterial2, HIVꢀ1 protease
inhibitors3, and ntihistaminic4. While, isoxazoles are core
components of many natural products such as ibotenic acid5,
muscimol6, isoxazoleꢀ4ꢀcarboxylic acid7 and drugs like
25 valdecoxib8, leflunomide9, cloxacillin10. Several therapeutically
active compounds containing both 1,2,3ꢀtriazoles and another
heterocycles such as thiazole and isoxazole have been reported.11
The significant biological activities observed for 1,2,3ꢀtriazole
bisfunctional
modified
peptidomimetics
by
tandem
multicomponent reactions (MCRs). Peptidomimetics are of
primordial importance for the study of functions and structures of
proteins in chemical biology and can in many cases be used as
60 drug molecules.3,14 However, this synthesis is traditionally
and
isoxazoles
suggested
potential
bioactivity
and
attained through
a inefficient reaction ， requiring many
30 pharmaceutically active if these two scaffolds could be combined
in one molecule.
protecting groups. In modern therapeutic discovery, the rapid
assembly of drug without protecting groups is gaining
considerable interest. Tandem multicomponent reactions are one
65 type of the approaches to address this challenge.15
However, an efficient synthesis of such bisfunctional
molecules containing 1,2,3ꢀtriazole and isoxazole scaffolds from
readily accessible starting materials still remains elusive.
35 Recently, some chemoselective sequential reactions have been
developed to synthesis unsymmetrical bisfunctional molecules
which could achieve complete regiochemical control of the
coupling reactions in a timely and costeffective manner, while
providing broad functional group tolerance.12 These methods
40 depend on the difference of the reactivities of bifunctional linkers
such as bialkyne or biazide which leads to chemoselectivity in
sequential ligation reactions. Our group also developed an
efficient chemoselective method to generate alkynyl substituted
N
HN
N
O
MeOH, DBU
reflux
R
N3
+
NH2
N
+
O
R
O
Fig.1 Chemoselective synthesis of monotriazoles
70 Results and Discussion
The key feature in this strategy is to find a suitable method for the
construction of isoxazoles building blocks. Taking into account
recent reports of on the isoxazoles synthesis, we focused on the
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Table 1. Scope of chemoselective sequential reaction for the synthesis of
bisfunctional nitrogen heterocycles combining both 1,2,3ꢀtriazole and
isoxazoles motifs.
synthesis of the isoxazoles structure by hypervalent iodineꢀ
mediated cycloaddition of nitrile oxides to alkynes (scheme 1).16
Although many transition metals mediated isoxazoles syntheses
have been reported17 not all are viable in such a combination
since the residual metal catalysts could be toxic to both bacterial
and mammalian cells.18 Therefore from a biological perspective
the transition metals approach is not a preferred catalytic method
favored. In our initial experiment, we synthesized alkynyl
substituted 1,2,3ꢀtrazoles 4a by using 2ꢀpropynylamine 3a (all
N
HN
N
N
60
65
70
O
MeOH, DBU
reflux
R1 N3
+
NH2
+
5
O
R1
O
1
3
2
4
OH
H
N
PIFA
R5
10 components see Figure 2) as bisfunctional linkers which mixed
with 1.1 equiv azides 1a and 1.1 equiv diketene 2a under base
catalyst (1.1 equiv DBU) conditions in MeOH at reflux.
Subsequently, according to the report of Delft group, we
employed phenyliodine bis(trifluoroacetate) (PIFA, 1.5 equiv) as
15 catalyst to react with benzaldoxime 5a (1.5 equiv) led to the
isolation of bisfunctional molecule 6a in 83% yield after 1.5 h at
40oC (71% total yield). However, the alkyl azides can not work in
this reaction.
5
R5
N
N
H
N
N
R1
N
O
O
Entry
1
product
Yielda Yieldb
83
82
82
84
83
71
58
70
71
61
N
N
O
H
MeOH, DBU
reflux
N
N
Ph
Cl
N3
+
H2N
2
3
4
5
+
N
N
O
Cl
N
H
O
20
3a
1a
2a
N
N
4a
O
OH
H
O
6b
N
PIFA
40o
C
5a
N
N
25
N
O
H
N
N
Cl
O
6a
Scheme 1. Chemoselective synthesis of 1,2,3ꢀtriazole and isoxazoles
containing bisfunctional molecule
30
Transparent plate crystals of 6a were obtained. A small single
crystal was measured by Xꢀray crystallography (Figure 3). The
crystal structure clearly shows compound 6a with both 1,2,3ꢀ
triazole and isoxazoles scaffolds.
6
7
76
85
65
65
35
40
8
9
84
89
71
65
Figure 3. Xꢀray diffraction measurement of 6a.
45
It is noteworthy that, our system for isoxazoles synthesis is
more convenient than that literature reported. For example, in our
process only MeOH was used as solvent, there is no addition was
added. However, according to the report of Delft group16(a) and
Ciufolini group20, another amount of water or TFA was needed.
50 In addition, the reaction consumes shorter time and less catalyst.
That means the 1,2,3ꢀtrazoles modified alkynyl 4a is more active
than normal alkynyl for the isoxazoles synthesis. It is presumably
because of the electronic effects. For electronꢀwithdrawing
alkynyl will give significant high yields. There is an amido bond
55 in triazole modified alkyne, which may have electronꢀ
withdrawing effect.
10
80
66
N
N
Cl
N
H
N
N
O
O
6j
a The second step isolated yield b The total isolated yield
2
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Cl
Cl
N
3
N
Me
N
3
O N
2
N
3
3
NH
2
NH
N
3
2
NH
2
1a
1b
1c
OH
3a
1d
OH
1e
3b
3c
8b
5
10
15
OH
H
N
N
Cl
N
NH
Cl
NH
CHO
Cl
CHO
2
2
H
H
7a
7b
8a
O N
2
5b
5c
5a
N
3
O
O
CHO
CHO
N
COOH
NC
N
CHO
NC
3
3
OH
COOH
10a
10b
9a
8c
9c
8d
8e
9b
Figure 2. Components involved in the described chemoselective sequential reactions.
With these optimized conditions in hand, the scope of the
reaction is illustrated by the examples in Table 1. To our delight,
both aromatic and aliphatic alkynyl substituted amines were used
and gave satisfactory yields. However, the electronic properties
4
)
.
Having demonstrated the viability of chemoselective sequential
procedures for the 1,2,3ꢀtriazole and isoxazoles motifs containing
bisfunctional heterocycles generation, we next investigated
20 of the alkynyl substituted anilines for the second step had a 35 bisfunctionalꢀmodified peptidomimetics synthesis. Recently, our
significant influence on the yield of the reaction. The electronꢀ
donating 2ꢀ methylbutꢀ3ꢀynꢀ2ꢀamine 3b gave lower yield than 2ꢀ
propynylamine 3a (table 1, entries 2, 6). Moreover, it was shown
previously that different oximes have various reactivities. The
group discovered a six components reaction to generate 1,2,3ꢀ
triazoleꢀmodified peptidomimetics by conjugating two MCRs in
one pot.19 The chemoselective bisfunctional synthesis opens up an
opportunity to introduce this six components reaction to generate
25 electronꢀdeficient 4ꢀnitroꢀ benzaldoxime 5b gave higher yield 40 complex bisfunctionalꢀmodified peptidomimetics by combining
than others for the isoxazoles synthesis (table 1, entries 2, 9, 10).
The steric effects also had a significant influence on the yields of
both first and second cycloadditions (Table 1, entries 2, 3, 5, 10).
However, the electronic properties of the substituted azides had a
30 slight influence on the yields of the reaction (Table 1, entries 1ꢀ
45
three reactions in sequence process. In our recent study, we found
that the Ugi reaction was an efficient method for the construction
of peptide building blocks and peptoid molecules in one step.21
Therefore, Paraꢀazidoꢀbenzoic acid 9a was chosen as the “bridge
O
R8
O
R8
R7NH2
R8CHO
H
N
Oneꢀpot
H
N
N
R7
R10
N
R7
R10
7
8
Second MCR
N
First MCR
O
+
N
O
N
N3
O
H
N
N3
R10NC
H2N
Me
11
O
3a
2
O
12
50
55
60
65
70
10
HOOC
9a
OH
H
N
PIFA
R5
5
R7
N
N
O
O
N
R10
H
N
R5
N
N
N
H
R8
O
O
13
Cl
N
N
O
N
O
N
O
O
N
N
H
N
H
N
N
N
N
N
N
N
H
H
O
O
O
O
13a 47%
13b 43%
N
O
N
N
O
N
N
O
O
N
H
N
N
N
H
N
N
N
N
N
H
H
O
O
O
O
O
13c 49%
13d 45%
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Scheme 2 Bisfunctionalꢀmodified peptidomimetic synthesis by combination three reactions in sequence proces
molecule” to combine Ugi 4CR with 3CR monotriazole synthesis
opportunity
to
generate
such
bisfunctionalꢀmodified
to construct monotriazoleꢀmodified peptidomimetics blocks. The
Ugi reaction was preferred as the first MCR. Based on classical
peptidomimetic in a rapid and efficient process.
To further explore the possible conformational preorganization
5
reports on Ugi 4CR, 9a was reacted with 7, 8, and 10 in MeOH at 20 effect of bifunctionalꢀmodified peptidomimetics, other kinds of
room temperature to form intermediate 11. Then without
isolation of the intermediate, a oneꢀpot combination with 1.1
equiv of 3a, 1.1 equiv of diketene 2, and 1.1 equiv of DBU as the
10 second MCR at reflux, led to the intermediate monotriazoleꢀ
modified peptidomimetics 12. Next subsequent hypervalent
iodineꢀmediated cycloaddition with oxime gave a 1,2,3ꢀtriazole
and isoxazoles containing bisfunctionalꢀmodified peptidomimetic
13 in good yield (Scheme 3). In addition, the α,βꢀunsaturated
15 functional group, such as furaldehyde was tolerate in such
azido containing bifunctional molecules have been used to
instead of paraꢀazidoꢀbenzoic acid as “bridge molecule” to
combine the three reactions (Table 2). 2ꢀazidobenzoic acid 9b
was then incorporated in this combination with no difficulty as a
25 bridge molecule (Scheme 3). However, steric effects were
indicated by the slight reduction in yield. Encouraged by these
results, we attempted to carry out the analogous reaction with 4ꢀ
azidobenzaldehyde 8e (Scheme 4). Thus,
a triazole and
isoxazoles bisfunctionalꢀmodified peptidomimetics containing
process (13c). The tandem multicomponent reactions open an 30 sideꢀchain were successfully synthesized.
N
O
O
OH
H
PhNH2
PhCHO
CyNC
N
H2N
O
H
N
O
MeOH
rt
+
Ph
35
N
COOH
DBU
reflux
PIFA
N
N
O
Ph
H
N
N3
N
Ph
O
40
14a 39%
Scheme 3 Chemoselective sequential synthesis of bisfunctionalꢀmodified peptidomimetics by using 2ꢀazidobenzoic acid as a bridge molecule
N3
N
O
N
O
N
N
R5
R7NH2
O
OH
H
N
HN
H2N
O
R9
45
50
55
60
65
OHC
+
O
7
8
R5
MeOH
rt
N
R7
base
PIFA
reflux
R9COOH
NH
R10
R10NC
10
O
15
9
N
O
N
O
N
N
O
N
O
N
N
N
HN
O
Cl
HN
O
N
N
Ph
NH
O
O
Cl
15b 40%
NH
O
15a 43%
N
O
N
O
N
N
N
Ph
O
N
O
N
Ph
HN
N
HN
O
N
N
NH
O
Cl
15d 46%
NH
O
Cl
15c 42%
Scheme 4 Chemoselective sequential reaction for bisfunctionalꢀmodified peptidomimetics by using paraꢀazidobenzaldehyde as a bridge molecule
Finally, to evaluate this synthetic method, a Lipinski ruleꢀofꢀfive
analysis was performed to evaluate the druglikeness of all
compounds (Table 2). It was found that the products 6 were
peptidomimetics, only parameters NHD adhered to Lapinski’s
ruleꢀofꢀfive. All of the hydrogen bond acceptors for products 12,
13, 14 are 11 which is one more than the Lapinski’s Rule. The
MW of all the peptidomimetics are about 600, which also do not
70 within the parameters set by Lipinski. However, for the
4
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adhered the Rule of Lapinski. The result suggesting that
compounds 6 is very appropriate for highthroughput screening to
discover drug leads and biological probes.
40 Typical experimental procedure
Preparation of bisfunctional molecules 6. Azides (2.0 mmol),
diketene (2.2 mmol), alkynyl substituted amines (2.2 mmol),
DBU (2.2 mmol) in a seal tube with 4 mL MeOH and stirred at
reflux for 8 hours. Then, the solvent was removed in vacuo and
45 the residue was purified by column chromatography (hexanes /
ethyl acetate 2/ 1). Then to a solution of compound 5 (0.5 mmol),
oxime (0.75 mmol) and phenyliodine bis(trifluoroacetate) (0.75
mmol) in 3 mL MeOH. The reaction mixture was stirred at 40℃
1.5 hours. The solvent was removed in vacuo and the residue was
50 purified by column chromatograp hy (hexanes / ethyl acetate 2/ 1).
1-(4-chlorophenyl)-5-methyl-N-((3-phenylisoxazol-5-
yl)methyl)-1H-1,2,3-triazole-4-carboxamide (6a). White solid,
M.p. 176ꢀ178°C. Yield: 0.14 g, 71%. 1H NMR (500 MHz,
CDCl3) δ 7.93ꢀ7.91 (t, J = 6 Hz, 1H), 7.81ꢀ7.79 (m, 2H), 7.58ꢀ
55 7.57 (m, 2H), 7.46ꢀ7.42 (m, 5H), 6.59 (s, 1H), 4.86 (d, J = 6 Hz,
2H), 2.65 (s, 3H) ; 13C NMR (125 MHz, CDCl3) δ 168.5, 161.6,
160.2, 137.2, 136.2, 135.3, 132.9, 129.0, 127.9, 127.3, 125.8,
125.5, 99.4, 33.9, 8.9; ESIꢀMS: m/z =394 [M+1]+. Found: C,
60.86; H, 4.01; N, 17.64%. Calc. for C20H16ClN5O2, C, 60.99; H,
60 4.09; N, 17.78%.
Table 4. A "Lapinski type" analysis of the physical properties
Entry
1
2
3
4
5
6
7
8
Product
6a
6b
6c
6d
6e
6f
6g
6h
MWa
393
359
373
404
393
387
421
435
404
407
693
727
727
659
693
605
673
639
665
NHDb
NHAc
7
7
7
7
7
7
7
7
tPSAd
78.65
78.65
78.65
130.46
78.65
78.65
78.65
78.65
130.46
78.65
128.06
128.06
128.06
128.06
106.47
106.47
106.47
106.47
106.47
Log P e
4.03
3.38
4.15
8.52
4.11
3.92
5.45
5.58
8.33
4.22
6.35
7.71
6.95
6.11
6.35
4.08
5.88
5.26
5.23
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
9
6i
6k
7
7
10
11
12
13
14
15
16
17
18
19
13a
13b
13c
13d
14a
15a
15b
15c
15d
11
11
11
11
11
11
11
11
11
5
a Molecular Weight. b Number of Hꢀdonors. c Number of Hꢀacceptors. d
polar surface area were given by ChemBioOffice 2008. e Partition
coefficient was tested in nꢀoctyl alcohol–water system by HPLC analysis.
5-methyl-1-phenyl-N-((3-phenylisoxazol-5-yl)methyl)-1H-
1,2,3-triazole-4-carboxamide (6b). White solid, M.p. 134ꢀ
1
136°C. Yield: 0.10 g, 58%. H NMR (500 MHz, CDCl3) δ 7.97ꢀ
Conclusions
7.95 (t, J = 6 Hz, 1H), 7.81ꢀ7.78 (m, 2H), 7.62ꢀ7.58 (m, 3H),
65 7.48ꢀ7.44 (m, 5H), 6.60 (s, 1H), 4.86 (d, J = 6 Hz, 2H), 2.66 (s,
3H) ; 13C NMR (125 MHz, CDCl3) δ 168.6, 161.6, 160.4, 137.0,
136.2, 134.5，129.1, 129.0, 128.7, 127.9, 125.9, 124.3, 99.4, 8.8;
ESIꢀMS: m/z =360 [M+1]+. Found: C, 66.66; H, 4.65; N, 19.35%.
Calc. for C20H17N5O2, C, 66.84; H, 4.77; N, 19.49%.
In conclusion, we have described an efficient chemoselective
10 approach to synthetize a novel bisfunctional molecules which
containing both 1,2,3ꢀtriazole and isoxazole motifs. The Lapinski
type analysis of the physical properties was given. Our strategy
employed alkynyl substituted amines as bifunctional linkers
which could generate 1,2,3ꢀtrazoles and isoxazoles by copperꢀfree
15 cycloaddition and hypervalent iodineꢀmediated cycloaddition
respectively. In particular, this methodology is suitable for
70 5-methyl-N-((3-phenylisoxazol-5-yl)methyl)-1-p-tolyl-1H-
1,2,3-triazole-4-carboxamide (6c). White solid, M.p. 146ꢀ
1
148°C. Yield: 0.13 g, 70%. H NMR (500 MHz, CDCl3) δ 8.03
synthetize
unsymmetrical
bisfunctionalꢀmodified
(s, 1H), 7.80ꢀ7.79 (m, 2H), 7.45ꢀ7.43 (t, J = 4 Hz, 3H), 7.38ꢀ7.28
(m, 4H), 6.59 (s, 1H), 4.86 (d, J = 6.5 Hz, 2H), 2.62 (s, 3H), 2.47
75 (s, 3H) ; 13C NMR (125 MHz, CDCl3) δ 168.7, 161.6, 160.5,
139.4, 136.9, 136.2, 132.0, 129.3, 129.0, 127.9, 125.9, 124.1,
99.4, 33.9, 20.3, 8.7; ESIꢀMS: m/z =374 [M+1]+. Found: C,
67.38; H, 5.26; N, 17.57%. Calc. for C21H19N5O2, C, 67.55; H,
5.13; N, 18.76%.
peptidomimetics by the combination of mlticomponent reactions
in sequence process, which allow direct access to complex
20 structures from simple building blocks and fully lives up to the
principle of “Green Chemistry” and atom economy. In addition,
the metal free process suggests this chemoselective reaction could
be a valuable tool for drug discovery.
80 5-methyl-1-(4-nitrophenyl)-N-((3-phenylisoxazol-5-
yl)methyl)-1H-1,2,3-triazole-4-carboxamide (6d). White solid,
M.p. 166ꢀ168°C. Yield: 0.14 g, 71%. 1H NMR (500 MHz,
CDCl3) δ 8.47 (d, J = 9 Hz, 2H), 7.96ꢀ7.94 (t, J = 6 Hz, 1H),
7.80ꢀ7.73 (m, 4H), 7.46ꢀ7.44 (t, J = 3 Hz, 3H), 6.59 (s, 1H), 4.86
85 (d, J = 6.5 Hz, 2H), 2.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
168.3, 161.6, 159.9, 147.3, 139.3, 137.7, 136.3, 129.1, 127.9,
125.8, 124.7, 124.2, 99.5, 33.9, 9.0; ESIꢀMS: m/z =405 [M+1]+.
Found: C, 59.26; H, 4.11; N, 20.63%. Calc. for C20H16N6O4, C,
59.40; H, 3.99; N, 20.78%.
Experimental section
25 General
All chemicals were commercially available and used without
further purification. Analytical thinꢀlayer chromatography were
performed on glass plates precoated with silica gel impregnated
with a fluorescent indicator (254 nm). The plates were visualized
30 by exposure to ultraviolet light. 1H NMR spectra were recorded
on Bruker DRX500 (500 MHz) and 13C NMR spectra on Bruker
DRX500 (125 MHz) spectrometer. Mass spectra were taken on a
Finnigan TSQ Quantum－MS in strument in the electrospray
ionization (ESI) mode. Elemental analyses were performed on a
35 Yanagimoto MT3CHN recorder. The distribution of clog P was
analyzed by high performance liquid chromatograph (HPLC)
on Agilent 1120 (Eclipse XDBꢀC18, G1214B VWD).
Melting points were determined uncorrected.
90 1-(2-chlorophenyl)-5-methyl-N-((3-phenylisoxazol-5-
yl)methyl)-1H-1,2,3-triazole-4-carboxamide (6e). White solid,
M.p. 124ꢀ126°C. Yield: 0.12 g, 61%. 1H NMR (500 MHz,
CDCl3) δ 8.12ꢀ8.10 (t, J = 6 Hz, 1H), 7.80ꢀ7.78 (m, 2H), 7.63ꢀ
7.62 (m, 1H), 7.57ꢀ7.54 (m, 1H), 7.50ꢀ7.47 (m, 1H), 7.44ꢀ7.42
95 (m, 4H), 6.60 (s, 1H), 4.86 (d, J = 6 Hz, 2H), 2.50 (s, 3H); 13
NMR (125 MHz, CDCl3) δ 168.8, 161.6, 160.3, 138.0, 136.5,
C
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mmol), diketene (1.1 mmol) and DBU (1.1 mmol) were added in
132.1, 131.2, 130.8, 129.7, 129.0, 128.2, 127.9, 127.1, 125.9,
99.4, 33.9, 8.1; ESIꢀMS: m/z =394 [M+1]+. Found: C, 60.91; H, 60 the seal tube and raised the reaction temperature to 80 C for 24
o
4.14; N, 17.70%. Calc. for C20H16ClN5O2, C, 60.99; H, 4.09; N,
17.78%.
5-methyl-1-phenyl-N-(2-(3-phenylisoxazol-5-yl)propan-2-yl)-
hours. The solvent was removed in vacuo and the residue was
purified by column chromatography (hexanes / ethyl acetate 3/ 1)
to give intermediates 12. Then, to a solution of compound 12 (0.5
mmol) Last, to a solution of compound 12 (0.5 mmol), oxime
5
1H-1,2,3-triazole-4-carboxamide (6f). White solid, M.p. 180ꢀ
1
182°C. Yield: 0.13 g, 65%. H NMR (500 MHz, CDCl3) δ 7.83ꢀ 65 (0.75 mmol) and phenyliodine bis(trifluoroacetate) (0.75 mmol)
7.81 (m, 2H), 7.63 (s, 1H), 7.58ꢀ7.56 (m, 2H), 7.45ꢀ7.40 (m, 5H),
in 3 mL MeOH. The reaction mixture was stirred at 60℃ for 4
hours. The solvent was removed in vacuo and the residue was
purified by column chromatograp hy (hexanes / ethyl acetate 2/
1).
2.58 (s, 3H), 1.93 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 175.1,
10 161.3, 159.5, 137.6, 136.0, 135.2, 133.0, 129.0, 128.2, 127.8,
125.9, 125.5, 97.5, 50.9, 26.4, 8.7; ESIꢀMS: m/z =389 [M+1]+.
Found: C, 68.07; H, 5.54; N, 17.97%. Calc. for C22H21N5O2, C, 70 1-(4-((2-(cyclohexylamino)-2-oxo-1-
68.20; H, 5.46; N, 18.08%.
phenylethyl)(phenyl)carbamoyl)phenyl)-5-methyl-N-((3-
5-methyl-1-phenyl-N-(3-(3-phenylisoxazol-5-yl)phenyl)-1H-
15 1,2,3-triazole-4-carboxamide (6g). White solid, M.p. 180ꢀ
182°C. Yield: 0.14 g, 65%. H NMR (500 MHz, CDCl3) δ 9.25
phenylisoxazol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
(13a). White solid, M.p. 132ꢀ134°C. Yield: 0.16 g, 47%. 1H
NMR (500 MHz, CDCl3) δ 7.78ꢀ7.76 (m, 2H), 7.73ꢀ7.71 (t, J = 6
1
(s, 1H), 8.34 (s, 1H), 7.89 (d, J = 6 Hz, 2H), 7.75ꢀ7.60 (m, 5H), 75 Hz, 1H), 7.52 (d, J = 8.5 Hz 2H), 7.43ꢀ7.40 (t, J = 4 Hz, 3H),
7.50ꢀ7.48 (m, 6H), 6.92 (s, 1H), 2.71 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 169.0, 162.0, 158.4, 137.5, 137.4, 136.6 134.5,
20 129.2, 129.0, 128.8, 127.9, 127.3, 125.9, 124.3, 120.6, 120.3,
116.0, 97.0, 8.9; ESIꢀMS: m/z =422 [M+1]+. Found: C,71.11; H,
7.25ꢀ7.24 (m, 8H), 7.03 (s, 4H), 6.54 (s, 1H), 6,19(s, 1H), 6.53 (s,
1H), 5.60 (d, J = 8 Hz 1H), 4.79 (d, J = 6 Hz, 2H), 3.91ꢀ3.87 (m,
1H), 2.52 (s, 3H), 1.98ꢀ1.90 (m, 2H), 1.67ꢀ1.60 (m, 3H), 1.38ꢀ
1.33 (m, 2H), 1.16ꢀ1.05 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
4.39; N, 16.75%. Calc. for C25H19N5O2, C, 71.25; H, 4.54; N, 80 168.6, 168.4, 167.2, 161.6, 160.2, 139.6, 137.1, 136.1, 134.8,
16.62%.
133.5, 129.4, 129.0, 128.9, 127.9, 127.7, 126.7, 125.8, 123.3,
99.4, 65.7, 48.0, 33.8, 31.9, 24.5, 23.8, 23.7, 8.7; ESIꢀMS: m/z
=716 [M+23]+. Found: C, 70.87; H, 5.59; N, 14.05%. Calc. for
C41H39N7O4, C, 70.98; H, 5.67; N, 14.13%.
1-(2-chlorophenyl)-5-methyl-N-((3-phenylisoxazol-5-
25 yl)methyl)-1H-1,2,3-triazole-4-carboxamide (6h). White solid,
M.p. 184ꢀ186°C. Yield: 0.15 g, 71%. 1H NMR (500 MHz,
CDCl3) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.89 (d, J = 6 Hz, 2H), 7.75ꢀ 85 N-((3-(2-chlorophenyl)isoxazol-5-yl)methyl)-1-(4-((2-
7.66 (m, 2H), 7.50ꢀ7.38 (m, 7H), 6.93 (s, 1H), 2.69 (s, 3H), 2.49
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 169.0, 162.0, 158.5,
30 139.5, 137.5, 137.3 136.6, 132.0, 129.3, 129.0, 128.8, 128.2,
127.9, 127.3, 125.9, 124.1, 120.6, 120.3, 116.0, 97.0, 20.3, 8.8;
(cyclohexylamino)-2-oxo-1-
phenylethyl)(phenyl)carbamoyl)phenyl)-5-methyl-1H-1,2,3-
triazole-4-carboxamide (13b). White solid, M.p. 114ꢀ116°C.
Yield: 0.16 g, 43%. 1H NMR (500 MHz, CDCl3) δ 7.78ꢀ7.75 (t, J
ESIꢀMS: m/z =436 [M+1]+. Found: C,71.85; H, 4.98; N, 15.93%. 90 = 6 Hz, 1H), 7.69ꢀ7.67 (m, 1H), 7.51 (d, J = 8.5 Hz 2H), 7.46ꢀ
Calc. for C26H21N5O2, C, 71.71; H, 4.86; N, 16.08%.
7.44 (m, 1H), 7.36ꢀ7.31 (m, 2H), 7.24ꢀ7.21 (m, 7H), 7.02 (s, 5H),
6.68 (s, 1H), 6,19(s, 1H), 5.65 (d, J = 8 Hz 1H), 4.81 (d, J = 6 Hz,
2H), 3.89ꢀ3.86 (m, 1H), 2.51 (s, 3H), 1.97ꢀ1.89 (m, 2H), 1.66ꢀ
1.62 (m, 3H), 1.37ꢀ1.32 (m, 2H), 1.15ꢀ1.07 (m, 3H); 13C NMR
5-methyl-N-((3-(4-nitrophenyl)isoxazol-5-yl)methyl)-1-
35 phenyl-1H-1,2,3-triazole-4-carboxamide (6i). White solid, M.p.
1
168ꢀ170°C. Yield: 0.13 g, 65%. H NMR (500 MHz, CDCl3) δ
8.34 (d, J = 6 Hz, 2H), 8.00 (d, J = 9 Hz, 2H), 7.88 (s, 1H), 7.61 95 (125 MHz, CDCl3) δ 168.6, 167.6, 167.3, 160.2, 139.6, 137.1,
(d, J = 7 Hz, 3H), 7.49ꢀ7.47 (m, 2H), 6.69 (s, 1H), 4.88 (d, J = 6
Hz, 2H), 2.67 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.7,
40 160.5, 159.8, 147.8, 136.9, 136.3, 134.4, 134.0, 130.7, 128.8,
126.7, 124.2, 123.2, 99.6, 33.9, 8.7; ESIꢀMS: m/z =405 [M+1]+.
136.1, 134.8, 133.5, 131.9, 130.0, 129.9, 129.4, 129.3, 128.9,
127.6, 127.2, 126.6, 126.1, 123.3, 102.6, 65.7, 48.0, 33.8, 31.8,
24.5, 23.8, 23.7, 8.7; ESIꢀMS: m/z =750 [M+23]+. Found: C,
67.89; H, 5.45; N, 13.23%. Calc. for C41H38ClN7O4, C, 67.62; H,
Found: C, 59.21; H, 4.07; N, 20.67%. Calc. for C20H16N6O4, C, 100 5.26; N, 13.46%.
59.40; H, 3.99; N, 20.78%.
1-(4-((2-(cyclohexylamino)-1-(furan-2-yl)-2-
N-((3-(2-chlorophenyl)isoxazol-5-yl)methyl)-5-methyl-1-p-
45 tolyl-1H-1,2,3-triazole-4-carboxamide (6j). White solid, M.p.
128ꢀ130°C. Yield: 0.13 g, 66%. H NMR (500 MHz, CDCl3) δ
oxoethyl)(phenyl)carbamoyl)phenyl)-5-methyl-N-((3-
phenylisoxazol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
(13c). White solid, M.p. 116ꢀ118°C. Yield: 0.18 g, 49%. 1H NMR
1
7.95 (d, J = 4.5 Hz, 1H), 7.73ꢀ7.71 (m, 1H), 7.48 (d, J = 8 Hz 105 (500 MHz, CDCl3) δ 7.80ꢀ7.78 (t, J = 6.5 Hz, 1H), 7.76ꢀ7.75 (m,
1H), 7.39ꢀ7.33 (m, 6H), , 6.73 (s, 1H), 4.89 (d, J = 6 Hz, 2H),
2.63 (s, 3H), 2.47 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 167.8,
50 160.4, 160.2, 139.4, 136.9, 136.2, 132.0, 131.9, 130.0, 129.8,
129.4, 129.2, 127.3, 126.1, 124.1, 102.6, 33.9, 20.3, 8.7; ESIꢀMS:
2H), 7.52ꢀ7.50 (t, J = 6.5 Hz 2H), 7.42ꢀ7.41 (m, 3H), 7.34ꢀ7.33
(m, 1H), 7.25ꢀ7.23 (m, 2H), 7.11ꢀ7.09 (m, 3H), 7.06 (s, 2H), 6.53
(s, 1H), 6.38 (d, J = 8 Hz 1H), 6.30 (s, 1H), 6.27ꢀ6.26 (m, 1H),
6.02 (d, J = 8 Hz, 1H), 4.78 (d, J = 6.5 Hz, 2H), 3.88ꢀ3.84 (m,
m/z =408 [M+1]+. Found: C, 61.65; H, 4.37; N, 17.03%. Calc. for 110 1H), 2.52 (s, 3H), 1.97ꢀ1.91 (m, 2H), 1.71ꢀ1.66 (m, 2H), 1.61ꢀ
C21H18ClN5O2, C, 61.84; H, 4.45; N, 17.17%.
1.58 (m, 1H), 1.38ꢀ1.33 (m, 2H), 1.19ꢀ1.44 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.4, 165.1, 160.2, 146.8, 139.6, 137.1,
136.5, 136.1, 135.0, 129.0, 128.5, 127.9, 127.8, 126.9, 125.8,
123.4, 111.4, 109.9, 99.4, 59.16, 47.9, 33.9, 31.8, 24.5, 23.7, 8.7;
Bisfunctional modified peptidomimetics 13, 14, 15. Amine (1
55 mmol), aldehyde (1 mmol) were dissolved in a seal tube with 2
mL MeOH and stirred at room temperature for 30 minutes. Then
Acid (1 mmol) and isocyanide (1 mmol) were added. The mixture 115 ESIꢀMS: m/z =706 [M+23]+. Found: C, 68.35; H, 5.58; N,
was stirred for 24 hours. Then corresponding aniline (0.55
14.53%. Calc. for C39H37N7O5, C, 68.51; H, 5.45; N, 14.34%.
6
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oxoethyl)phenyl)-5-methyl-N-((3-phenylisoxazol-5-yl)methyl)-
yl)(phenyl)carbamoyl)phenyl)-5-methyl-N-((3-phenylisoxazol- 60 1H-1,2,3-triazole-4-carboxamide (15c). White solid, M.p. 196ꢀ
1-(4-((1-(cyclohexylamino)-3-methyl-1-oxobutan-2-
1
5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (13d). White
solid, M.p. 106ꢀ108°C. Yield: 0.15 g, 45%. H NMR (500 MHz,
CDCl3) δ 7.87ꢀ7.85 (t, J = 6 Hz, 1H), 7.76ꢀ7.74 (m, 2H), 7.41ꢀ
7.40 (t, J = 3.5 Hz, 5H), 7.24 (d, J = 8.5 Hz, 2H), 7.21ꢀ7.15 (m,
198°C. Yield: 0.14 g, 42%. H NMR (500 MHz, CDCl3) δ 7.81ꢀ
7.79 (m, 3H), 7.46ꢀ7.45 (m, 3H), 7.39ꢀ7.38 (m, 2H), 7.32ꢀ7.31
(m, 2H), 7.22ꢀ7.20 (m, 2H), 6.59 (s, 1H), 6.09 (s, 1H), 5.81 (s,
1H), 4.84 (d, J = 6 Hz, 2H), 2.58 (s, 3H), 1.91 (s, 3H), 1.39 (s,
1
5
5H), 6.94 (s, 1H), 6.53 (s, 1H), 4.79 (d, J = 6.5 Hz, 2H), 4.48 (d, J 65 9H); 13C NMR (125 MHz, CDCl3) δ 170.1, 168.4, 167.1, 161.6,
= 11 Hz, 2H), 3.84ꢀ3.78 (m, 1H), 2.52 (s, 3H), 1.92ꢀ1.88 (m, 2H),
1.71ꢀ1.68 (m, 2H), 1.59ꢀ1.56 (m, 1H), 1.38ꢀ1.35 (m, 2H), 1.26ꢀ
160.2, 137.6, 137.1, 136.1, 135.8, 134.4, 133.5, 130.7, 129.0,
128.3, 127.9, 125.8, 124.0, 99.5, 63.0, 50.9, 33.9, 27.7, 22.2, 8.7;
ESIꢀMS: m/z =662 [M+23]+. Found: C, 63.57; H, 5.51; N,
15.17%. Calc. for C34H34ClN7O4, C, 63.79; H, 5.35; N, 15.32%.
10 1.18 (m, 3H), 1.04ꢀ1.02 (t, J = 7 Hz 6H); 13C NMR (125 MHz,
CDCl3) δ 169.6, 168.4, 168.2, 161.6, 160.2, 140.3, 137.2, 136.1,
135.0, 129.0, 128.7, 128.1, 127.9, 126.8, 125.8, 123.5, 99.4, 70.3, 70 1-(4-(1-(N-(4-chlorophenyl)acetamido)-2-(cyclohexylamino)-
47.0, 33.9, 31.9, 25.9, 24.5, 23.7, 19.1, 18.9, 8.7; ESIꢀMS: m/z
=682 [M+23]+. Found: C, 69.03; H, 6.51; N, 14.75%. Calc. for
15 C38H41N7O4, C, 69.18; H, 6.26; N, 14.86%.
2-oxoethyl)phenyl)-5-methyl-N-((3-phenylisoxazol-5-
yl)methyl)-1H-1,2,3-triazole-4-carboxamide (15d). White
1
solid, M.p. 180ꢀ182°C. Yield: 0.15 g, 46%. H NMR (500 MHz,
1-(2-((2-(cyclohexylamino)-2-oxo-1-
CDCl3) δ 7.87ꢀ7.84 (t, J = 6 Hz,, 1H), 7.81ꢀ7.79 (m, 2H), 7.46ꢀ
75 7.45 (m, 3H), 1.39 (d, J = 7.5 Hz, 2H), 7.32 (d, J = 8 Hz, 2H),
7.21 (d, J = 7 Hz, 2H), 7.8ꢀ7.13 (m, 2H), 6.59 (s, 1H), 6.16 (s,
1H), 5.87 (7.32 (d, J = 7 Hz, 2H), 4.84 (d, J = 6 Hz, 2H), 3.85ꢀ
3.84 (m, 1H), 2.58 (s, 3H), 2.01ꢀ1.99 (m, 1H), 1.99 (s, 3H), 1.87ꢀ
1.86 (m, 1H), 1.69ꢀ1.61 (m, 3H), 1.39ꢀ1.35 (m, 2H), 1.22ꢀ1.14
phenylethyl)(phenyl)carbamoyl)phenyl)-5-methyl-N-((3-
phenylisoxazol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
(14a). White solid, M.p. 108ꢀ110°C. Yield: 0.13 g, 39%. 1H
20 NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.80ꢀ7.78 (t, J = 3 Hz,
2H), 7.43ꢀ7.42 (m, 3H), 7.34ꢀ7.30 (m, 4H), 7.25ꢀ7.23 (m, 1H),
7.15ꢀ7.13 (m, 3H), 7.12ꢀ7.09 (m, 3H), 7.02ꢀ6.96 (m, 3H), 6.63 (s, 80 (m, 3H); 13C NMR (125 MHz, CDCl3), δ 170.2, 168.4, 167.0,
1H), 5.95 (s, 1H), 5.71 (d, J = 7.5 Hz, 1H), 4.87ꢀ4.85 (m, 2H),
3.84ꢀ3.80 (m, 1H), 2.52 (s, 3H), 1.91ꢀ1.86 (m, 2H), 1.62ꢀ1.53 (m,
25 3H), 1.32ꢀ1.29 (m, 2H), 1.11ꢀ1.04 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.6, 167.1, 166.0, 161.7, 160.4, 139.3, 138.4, 136.5,
161.6, 160.2, 137.7, 137.1, 136.1, 135.7, 134.4, 133.5, 130.8,
129.1, 128.3, 127.9, 125.8, 124.1, 99.5, 62.7, 48.0, 33.9, 31.8,
24.4, 23.8, 22.2, 8.7; ESIꢀMS: m/z =688 [M+23]+. Found: C,
65.16; H, 5.57; N, 14.53%. Calc. for C36H36ClN7O4, C, 64.91; H,
133.9, 131.7, 129.1, 129.0, 128.5, 127.9, 127.4, 126.5, 125.9, 85 5.45; N, 14.72%.
125.5, 99.6, 65.6, 48.0, 33.9, 31.7, 24.5, 23.8, 8.6; ESIꢀMS: m/z
=716 [M+23]+. Found: C, 70.76; H, 5.58; N, 14.05%. Calc. for
30 C41H39N7O4, C, 70.98; H, 5.67; N, 14.13%.
Acknowledgement
We thank financial supported by the Jiangsu Province Key Laboratory of
Fine Petrochemical Engineering (KF1101) and Nanjing University of
Science and Technology research funding (2011ZDJH07). We also thank
90 the Analysis and Testing Center of Nanjing University of Science and
Technology assistance with NMR spectroscopic analysis.
1-(4-(2-(tert-butylamino)-2-oxo-1-(N-
phenylacetamido)ethyl)phenyl)-5-methyl-N-((3-
phenylisoxazol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide
(15a). White solid, M.p. 166ꢀ168°C. Yield: 0.15 g, 43%. 1H
35 NMR (500 MHz, CDCl3) δ 7.95ꢀ7.92 (t, J = 3 Hz, 2H), 7.80ꢀ7.78
(m, 2H), 7.45ꢀ7.43 (m, 3H), 7.38 (d, J = 8.5 Hz, 2H), 7.28ꢀ7.24
(m, 6H), 7.11 (s, 1H), 6.58 (s, 1H), 6.10 (s, 1H), 6.03 (s, 1H),
4.84 (d, J = 6.5 Hz, 2H), 2.55 (s, 3H), 1.90 (s, 3H), 1.39 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 170.4, 168.5, 167.3, 161.6, 160.3,
40 139.2, 137.1, 136.1, 134.1, 130.7, 129.2, 129.0, 128.2, 127.9,
127.4, 125.8, 123.8, 99.4, 63.3, 50.8, 33.9, 27.7, 22.3, 8.7; ESIꢀ
MS: m/z =728 [M+23]+. Found: C, 67.57; H, 5.92; N, 16.03%.
Calc. for C34H35N7O4, C, 67.42; H, 5.82; N, 16.19%.
Notes and references
a Chemical Engineering College, Nanjing University of Science and
Technology, Nanjing, 210094, P. R. China. phone: +86ꢀ25ꢀ84315514;
95 fax: +86ꢀ25ꢀ84315030; Eꢀmail: c.cai@mail.njust.edu.cn
b Jiangsu Province Key Laboratory of Fine Petrochemical Engineering,
Changzhou University, Changzhou 213164, P. R. China
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
100 DOI: 10.1039/b000000x/
1-(4-(2-(tert-butylamino)-1-(N-(4-chlorophenyl)acetamido)-2-
45 oxoethyl)phenyl)-N-((3-(2-chlorophenyl)isoxazol-5-yl)methyl)-
5-methyl-1H-1,2,3-triazole-4-carboxamide (15b). White solid,
M.p. 154ꢀ156°C. Yield: 0.13 g, 40%. 1H NMR (500 MHz,
CDCl3) δ 7.83 (s, 1H), 7.70 (d, J = 3.5 Hz, 1H), 7.49ꢀ7.47 (m,
1H), 7.40ꢀ7.35 (m, 4H), 7.33ꢀ7.30 (m, 2H), 7.20 (d, J = 7 Hz,
50 2H), 7.07 (s, 2H), 6.72 (d, J = 0.5 Hz, 1H), 6.09 (s, 1H), 5.85 (s,
1H), 4.87 (d, J = 6 Hz, 2H), 2.56 (s, 3H), 1.89 (s, 3H), 1.38 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 170.1, 167.7, 167.2, 160.2,
137.6, 137.1, 136.1, 135.8, 134.4, 133.4, 131.9, 130.8, 130.7,
129.9, 129.4, 128.3, 127.2, 126.1, 124.0, 102.6, 63.0, 50.9, 33.8,
55 27.6, 22.3, 8.7; ESIꢀMS: m/z =696 [M+23]+. Found: C, 60.71; H,
5.02; N, 14.39%. Calc. for C34H33Cl2N7O4, C, 60.54; H, 4.93; N,
14.53%.
1 Q. Wan, J. Chen, G. Chen, and S. J. Danishefsky, J. Org. Chem.
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